Field of the Invention
The present invention is in the field of pharmacotherapy of Gram-negative bacterial infections. More specifically, the present invention is directed to novel liposomal formulations of polymyxin and uses thereof.
Description of the Related Art
Infections caused by multidrug-resistant (MDR) Gram-negative bacteria such as Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae have presented a critical challenge to the world for decades (5, 7, 17). Among different infections caused by multidrug-resistant Gram-negative bacteria, pulmonary infections are especially problematic and are associated with the highest mortality rate (11, 15, 28). Since no first-line antibiotic is effective, polymyxin B is often used as the last resort treatment for infections caused by multidrug-resistant Gram-negative bacteria (19, 30).
Polymyxin B (USP) is commercially available as a mixture of several closely related polypeptides, obtained from cultures of various strains of Bacillus polymyxa and related species (24). The major components of polymyxin B (USP) are polymyxin B1, B2, B3 and isoleucine-B1 (PB1, PB2, PB3 and ile-PB1(23); the proportions of which are 73.5%, 13.7%, 4.2% and 8.6%, respectively (14).
Most clinical isolates of Gram-negative bacilli, including those that are multidrug-resistant, are susceptible to polymyxin B (6, 13, 26). Intravenous polymyxin B sulfate (USP) is commonly used for the treatment of critically ill patients with pulmonary infections (12). Despite good in vitro susceptibility, previous studies demonstrated that polymyxin B was associated with reduced efficacy in the treatment of pulmonary infections (12, 16, 27). A possible explanation for poor therapeutic outcomes is limited penetration of polymyxin B into the site of infection, i.e., the epithelial lining fluid (ELF).
Liposomes are microscopic spheres which were developed as drug delivery vehicles/systems in the 1980s. The first liposome-based pharmaceuticals were approved for commercial use in the 1990s. Liposomes are considered a promising drug delivery system since they passively target tumor tissue by using the pathophysiological characteristics of solid tumors such as hyperplasia and increased vascular permeability, but also a defect in lymphatic drainage. These features facilitate extravasation of nanoparticles and the liposomes can be retained in the tissue for longer time due to the enhanced permeability and retention effect (EPR). Thus, liposome encapsulation could potentially alter the pharmacokinetics and biodistributions of antimicrobials, compared with standard formulations (2, 10). Increased uptake by activated tissue macrophages would allow higher antimicrobial concentrations to be achieved in pulmonary tissues (4, 8) and presumably improve treatment efficacy.
Nephrotoxicity is the major concern hindering considerable dose escalation to circumvent poor concentration achieved in the epithelial lining fluid. Reduced drug uptake into the kidneys would decrease or delay injury to the kidneys.
Thus, there is a recognized need in the art for improved formulations of polymyxin. Specifically, the prior art is deficient in the lack of liposomal formulations of polymyxin that enhance drug delivery to the site of an infection susceptible to the polymyxin. The present invention fulfills this longstanding need and desire in the art.